U.S. patent application number 16/319821 was filed with the patent office on 2019-07-25 for method of producing fluorine-containing pyrazole carboxylic acid halide.
This patent application is currently assigned to AGC Inc.. The applicant listed for this patent is AGC INC.. Invention is credited to Yuichiro ISHIBASHI, Yasushi MATSUMURA, Tamaki SHIMIZU, Osamu YOKOKOJI.
Application Number | 20190225585 16/319821 |
Document ID | / |
Family ID | 61016510 |
Filed Date | 2019-07-25 |
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United States Patent
Application |
20190225585 |
Kind Code |
A1 |
ISHIBASHI; Yuichiro ; et
al. |
July 25, 2019 |
METHOD OF PRODUCING FLUORINE-CONTAINING PYRAZOLE CARBOXYLIC ACID
HALIDE
Abstract
The invention relates to a method of producing a compound
represented by the formula (a) by reacting a compound represented
by the formula (c) with a halogenating agent in a non-aqueous
system: ##STR00001## wherein R.sup.1 is a fluoroalkyl group having
1 to 3 carbon atoms, R.sup.2 is a hydrogen atom or an alkyl group
having 1 to 6 carbon atoms, R.sup.3 is an alkyl group having 1 to 6
carbon atoms, and X is a halogen atom.
Inventors: |
ISHIBASHI; Yuichiro; (Tokyo,
JP) ; MATSUMURA; Yasushi; (Tokyo, JP) ;
YOKOKOJI; Osamu; (Tokyo, JP) ; SHIMIZU; Tamaki;
(Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AGC INC. |
Tokyo |
|
JP |
|
|
Assignee: |
AGC Inc.
Tokyo
JP
|
Family ID: |
61016510 |
Appl. No.: |
16/319821 |
Filed: |
July 26, 2017 |
PCT Filed: |
July 26, 2017 |
PCT NO: |
PCT/JP2017/026963 |
371 Date: |
January 22, 2019 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 39/00 20130101;
C07D 231/14 20130101 |
International
Class: |
C07D 231/14 20060101
C07D231/14; C07B 39/00 20060101 C07B039/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 29, 2016 |
JP |
2016-150521 |
Claims
1. A method of producing a compound represented by the formula (a),
which comprises reacting a compound represented by the formula (c)
with a halogenating agent in a non-aqueous system: ##STR00013##
wherein R.sup.1 is a fluoroalkyl group having 1 to 3 carbon atoms,
R.sup.2 is a hydrogen atom or an alkyl group having 1 to 6 carbon
atoms, R.sup.3 is an alkyl group having 1 to 6 carbon atoms, and X
is a halogen atom.
2. The method according to claim 1, wherein R.sup.1 is a
monofluoromethyl group, a difluoromethyl group or a trifluoromethyl
group, R.sup.2 is a hydrogen atom, a methyl group, an ethyl group,
an n-propyl group or an isopropyl group, and R.sup.3 is a methyl
group, an ethyl group, an n-propyl group or an isopropyl group.
3. The method according to claim 2, wherein the halogenating agent
is a chlorinating agent, and X is a chlorine atom.
4. The method according to claim 3, wherein the chlorinating agent
is chlorine (Cl.sub.2), p-toluenesulfonyl chloride, methanesulfonyl
chloride, oxalyl chloride, phosgene, sulfur dichloride, sulfur
monochloride, thionyl chloride, sulfuryl chloride or phosphorus
pentachloride.
5. The method according to claim 4, wherein the reaction is carried
out in the presence of a non-aqueous solvent.
6. The method according to claim 5, wherein the non-aqueous solvent
is an aromatic halide or an aliphatic halide.
7. The method according to claim 1, wherein the halogenating agent
is a chlorinating agent, and X is a chlorine atom.
8. The method according to claim 7, wherein the chlorinating agent
is chlorine (Cl.sub.2), p-toluenesulfonyl chloride, methanesulfonyl
chloride, oxalyl chloride, phosgene, sulfur dichloride, sulfur
monochloride, thionyl chloride, sulfuryl chloride or phosphorus
pentachloride.
9. The method according to claim 8, wherein the reaction is carried
out in the presence of a non-aqueous solvent.
10. The method according to claim 9, wherein the non-aqueous
solvent is an aromatic halide or an aliphatic halide.
11. The method according to claim 1, wherein the reaction is
carried out in the presence of a non-aqueous solvent.
12. The method according to claim 11, wherein the non-aqueous
solvent is an aromatic halide or an aliphatic halide.
Description
TECHNICAL FIELD
[0001] The present invention relates to a method of producing
fluorine-containing pyrazolecarboxylic acid halides useful as
pharmaceutical or agrochemical intermediates.
BACKGROUND ART
[0002] Fluorine-containing pyrazolecarboxylic acid halides such as
3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride and the
like are intermediates useful for pyrazolylcarboxanilide fungicides
(see, for example, Patent Documents 1 and 2).
[0003] Moreover, Patent Document 3 discloses a method of obtaining
a compound represented by the following formula (b.sup.1) by
reacting a compound represented by the following formula (c.sup.1)
with sodium hypochlorite in an aqueous system.
##STR00002##
DOCUMENT LIST
Patent Document
[0004] Patent Document 1: WO 03/070705
[0005] Patent Document 2: WO 03/074491
[0006] Patent Document 3: CN 105541716 specification
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0007] A method of reacting a compound represented by the formula
(b.sup.1), which is obtained according to the method described in
Patent Document 3, with phosgene or thionyl chloride may be
conceived as a method of producing fluorine-containing
pyrazolecarboxylic acid halides as typified by a compound
represented by the following formula (a.sup.1)
(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride), as
shown in the following scheme.
##STR00003##
[0008] However, this scheme needs two-step reaction, and therefore,
more simple production method is desired from the industrial
aspect.
[0009] Fluorine-containing pyrazolylalkylketones as typified by a
compound represented by the formula (c.sup.1), i.e., pyrazole
derivatives wherein the 1-position is substituted with an alkyl
group, the 3-position is substituted with a fluoroalkyl group, and
the 4-position is substituted with an alkylketone group
(alkylcarbonyl group), seem to have a unique property. However, the
details have not been yet known.
[0010] The aim of the present invention is to provide a method
capable of more simply and efficiently producing
fluorine-containing pyrazolecarboxylic acid halides useful as
pharmaceutical or agrochemical intermediates.
Means of Solving the Problems
[0011] The present inventors have conducted intensive studies on
the reaction properties of fluorine-containing
pyrazolylalkylketones, and have found that fluorine-containing
pyrazolecarboxylic acid halides can be obtained by reacting
fluorine-containing pyrazolylalkylketones with a halogenating agent
in a non-aqueous system. That is, fluorine-containing
pyrazolecarboxylic acid halides can be obtained from
fluorine-containing pyrazolylalkylketones by one-step reaction.
[0012] Accordingly, the present invention comprises the following
inventions. [0013] [1] A method of producing a compound represented
by the formula (a), which comprises reacting a compound represented
by the formula (c) with a halogenating agent in a non-aqueous
system;
##STR00004##
[0013] wherein [0014] R.sup.1 is a fluoroalkyl group having 1 to 3
carbon atoms, [0015] R.sup.2 is a hydrogen atom or an alkyl group
having 1 to 6 carbon atoms, [0016] R.sup.3 is an alkyl group having
1 to 6 carbon atoms, and [0017] X is a halogen atom. [0018] [2] The
method according to the above-mentioned [1], wherein R.sup.1 is a
monofluoromethyl group, a difluoromethyl group or a trifluoromethyl
group, R.sup.2 is a hydrogen atom, a methyl group, an ethyl group,
an n-propyl group or an isopropyl group, and R.sup.3 is a methyl
group, an ethyl group, an n-propyl group or an isopropyl group.
[0019] [3] The method according to the above-mentioned [1] or [2],
wherein the halogenating agent is a chlorinating agent, and X is a
chlorine atom. [0020] [4] The method according to the
above-mentioned [3], wherein the chlorinating agent is chlorine
(Cl.sub.2), p-toluenesulfonyl chloride, methanesulfonyl chloride,
oxalyl chloride, phosgene, sulfur dichloride, sulfur monochloride,
thionyl chloride, sulfuryl chloride or phosphorus pentachloride.
[0021] [5] The method according to any one of the above-mentioned
[1] to [4], wherein the reaction is carried out in the presence of
a non-aqueous solvent. [0022] [6] The method according to the
above-mentioned [5], wherein the non-aqueous solvent is an aromatic
halide or an aliphatic halide.
Effect of the Invention
[0023] According to the production method of the present invention,
fluorine-containing pyrazolecarboxylic acid halides useful as
pharmaceutical or agrochemical intermediates can be produced
efficiently on industrial scale.
Description of Embodiments
[0024] In the present specification, a compound represented by the
formula (x) may also be referred to as compound (x). In the present
specification, numerical range shown by using "to" means the range
including the numerical values described before and after "to" as
minimum and maximum values.
[0025] The embodiments of the present invention are explained below
in detail.
[0026] The present invention provides a method of producing a
compound represented by the following formula (a) (hereinafter,
also simply referred to as "compound (a)"), i.e., a
fluorine-containing pyrazolecarboxylic acid halide, which comprises
reacting a compound represented by the following formula (c)
(hereinafter, also simply referred to as "compound (c)") with a
halogenating agent in a non-aqueous system.
##STR00005##
[0027] In the formula, R.sup.1 is a fluoroalkyl group having 1 to 3
carbon atoms.
[0028] The fluoroalkyl group means a group wherein one or more
hydrogen atoms of the alkyl group are replaced with fluorine
atoms.
[0029] R.sup.1 is preferably a monofluoromethyl group, a
difluoromethyl group or a trifluoromethyl group, particularly
preferably a difluoromethyl group or a trifluoromethyl group.
[0030] In the formula, R.sup.2 is a hydrogen atom or an alkyl group
having 1 to 6 carbon atoms.
[0031] R.sup.2 is preferably a hydrogen atom, a methyl group, an
ethyl group, an n-propyl group or an isopropyl group, particularly
preferably a methyl group.
[0032] In the formula, R.sup.3 is an alkyl group having 1 to 6
carbon atoms.
[0033] R.sup.3 is preferably a methyl group, an ethyl group, an
n-propyl group or an isopropyl group, particularly preferably a
methyl group.
[0034] In the formula, X is a halogen atom. Examples of the halogen
atom include a fluorine atom, a chlorine atom, a bromine atom and
an iodine atom.
[0035] X is preferably a chlorine atom or a bromine atom,
particularly preferably a chlorine atom.
[0036] As a preferable embodiment, the compound wherein RI- is a
monofluoromethyl group, a difluoromethyl group or a trifluoromethyl
group, R.sup.2 is a hydrogen atom, a methyl group, an ethyl group,
an n-propyl group or an isopropyl group, and R.sup.3 is a methyl
group, an ethyl group, an n-propyl group or an isopropyl group is
preferable. In this embodiment, R.sup.3 is particularly preferably
a methyl group.
[0037] Compound (c) can be obtained according to a known method
(for example, the method described in Patent Document 3).
[0038] Alternatively, compound (c) can be also obtained from a
compound represented by the following formula (c'). Compound (c')
corresponds to compound (c) protected by an acetal.
[0039] In the formula, n is an integer of 1 to 4.
##STR00006##
[0040] When compound (c') is used, then compound (c') is, for
example, preferably chemically converted to compound (c) under
acidic condition (deprotection). The obtained compound (c) can be
subjected to the production method of the present invention after
isolation or sequentially without isolation.
[0041] Specific examples of compound (c) include the following
compounds.
##STR00007##
[0042] Specific examples of compound (a) include the following
compounds. In the formulas, X is a halogen atom.
##STR00008##
[0043] The kind of the halogenating agent is not particularly
limited, and examples thereof include conventional halogenating to
agents (e.g., a fluorinating agent, a chlorinating agent, a
brominating agent, an iodinating agent). Among them, a chlorinating
agent and a brominating agent are preferable, and a chlorinating
agent is particularly preferable. In the production method of the
present invention, when the halogenating agent is a chlorinating
agent, then compound (a) wherein X is a chlorine atom is obtained,
and when the halogenating agent is a brominating agent, then
compound (a) wherein X is a bromine atom is obtained.
[0044] The chlorinating agent is preferably chlorine (Cl.sub.2),
p-toluenesulfonyl chloride (tosyl chloride), methanesulfonyl
chloride (mesyl chloride), oxalyl chloride, phosgene, sulfur
dichloride, sulfur monochloride, thionyl chloride, sulfuryl
chloride or phosphorus pentachloride. It is particularly preferably
sulfur monochloride, thionyl chloride or sulfuryl chloride, from
the aspect of easy handling, economic efficiency and reaction
work-up (isolation and purification of compound (a)).
[0045] The brominating agent is preferably bromine (Br.sub.2),
trichlorobromomethane, tetrabromomethane, phosphorus tribromide or
boron tribromide.
[0046] The amount of the halogenating agent to be used is
preferably 1 equivalent or more relative to compound (c), from the
aspect of conversion and selectivity of the reaction, preferably 10
equivalent or less, particularly preferably 6 equivalent or less,
relative to compound (c), from the aspect of inhibition of side
reaction. The above-mentioned equivalent means molar
equivalent.
[0047] For example, when sulfur monochloride is used as a
halogenating agent, it is preferably used in an amount of 3 to 6
mol, per 1 mol of compound (c).
[0048] The halogenating agent may be used alone or in combination
of two or more kinds thereof.
[0049] Moreover, the production method of the present invention is
preferably carried out in the presence of a basic compound, from
the aspect of yield of compound (a).
[0050] The basic compound is preferably a basic compound having
only proton affinity, but not having acidic property, specifically
preferably a nitrogen-containing compound (an amine compound),
particularly preferably a nitrogen-containing aromatic compound.
Specific examples of the basic compound include pyridine,
pyrimidine, pyridazine, pyrazine, oxazole, thiazole, quinoline and
the like.
[0051] The amount of the basic compound to be used is preferably
exceeding 0 to 0.25 mol, particularly preferably 0.01 to 0.15 mol,
per 1 mol of compound (c).
[0052] The production method of the present invention is carried
out in a non-aqueous system, from the aspect of inhibition of
hydrolysis of the produced compound (a). The non-aqueous system
herein means a system wherein water is substantively absent,
specifically, a system wherein its moisture content is maintained
at 1000 mass ppm or less. The moisture content in the system is
represented by mass ratio of water relative to all materials placed
in the system. The above-mentioned moisture content is measured by
Karl Fischer moisture measurement method.
[0053] The production method of the present invention is preferably
carried out in the presence of a non-aqueous solvent. The
non-aqueous solvent means a solvent other than water. The moisture,
content of the non-aqueous solvent (mass ratio of water relative to
the non-aqueous solvent) is preferably 1000 mass ppm or less.
[0054] The non-aqueous solvent is preferably a solvent inert to the
halogenating agent, and specific examples thereof include ether
solvents such as diethyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane and the like; aromatic hydrocarbon solvents
such as benzene, toluene, xylene, mesitylene and the like; aromatic
halides such as monochlorobenzene, dichlorobenzene and the like;
aliphatic hydrocarbon solvents such as hexane, heptane, octane,
cyclohexane and the like; and aliphatic halides such as methylene
chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and
the like.
[0055] The non-aqueous solvent is preferably an aromatic halide or
an aliphatic halide, particularly preferably monochlorobenzene,
dichloromethane or chloroform.
[0056] The amount of the non-aqueous solvent to be used is
preferably 1 to 50-fold amount (mass standard), particularly
preferably 2 to 15-fold amount (mass standard), relative to
compound (c).
[0057] In the production method of the present invention, the
procedure of mixing compound (c) and a halogenating agent is not
particularly limited.
[0058] For example, a procedure of adding a halogenating agent to
compound (c) or a solution containing compound (c) and a
non-aqueous solvent can be employed. The halogenating agent may be
added in the form of a solution in a non-aqueous solvent.
[0059] Alternatively, a procedure of adding compound (c) to a
halogenating agent or a solution containing a halogenating agent
and a non-aqueous solvent can also be employed. Compound (c) may be
added in the form of a solution in a non-aqueous solvent.
[0060] A method of mixing compound (c) and a halogenating agent may
be a method of mixing both in batch (batch mixing method), or a
method of mixing compound (c) or a halogenating agent by small
portions into the other (portioning mixing method).
[0061] In the portioning mixing method, the number of portions to
be mixed into the other is not particularly limited as long as it
is two or more, and the upper limit is usually five.
[0062] Specific examples of the portioning mixing method include a
method of dividing compound (c) or a solution containing compound
(c) and a non-aqueous solvent into two or more portions, and mixing
these portions into a halogenating agent.
[0063] In mixing of compound (c) and a halogenating agent, the one
may be added to the other under stirring, if necessary.
[0064] In the production method of the present invention, the
reaction temperature is preferably 0 to 250.degree. C.,
particularly preferably 0 to 200.degree. C., from the aspect of
efficient reaction progress due to inhibition of side reaction. The
reaction temperature may be varied during the reaction, if
necessary.
[0065] The reaction atmosphere is not particularly limited, and it
is preferably an inert gas (nitrogen etc.) atmosphere, in order to
maintain the conditions of the non-aqueous system, as mentioned
above.
[0066] The pressure of the reaction atmosphere may be increased
pressure, reduced pressure or atmospheric pressure, preferably
atmospheric pressure.
[0067] In the production method of the present invention, the
method of isolating compound (a) from the reaction system after the
completion of the reaction is not particularly limited. For
example, compound (a) with high purity can be easily isolated by
solvent extraction or crystallization.
[0068] Compound (a) obtained by the production method of the
present invention is useful as intermediates for antimicrobials,
fungicides, insecticides, or bulk pharmaceuticals or agrochemicals,
for example, useful as intermediates for the following
antimicrobials, fungicides, or bulk pharmaceuticals or
agrochemicals.
##STR00009## ##STR00010##
[0069] As a method of producing antimicrobials, fungicides,
insecticides, or bulk pharmaceuticals or agrochemicals using
compound (a), a method of reacting compound (a) with each of amines
represented by the following formulas can be employed. Each
reaction can be carried out according to a known method.
##STR00011##
[0070] According to the production method of the present invention,
the number of steps is reduced, and compound (a) can be efficiently
produced, compared to conventional art. That is, chloroalkane
(chloroform, etc.) generated as a by-product in an oxidation
reaction using sodium hypochlorite, as known in the conventional
art, is not substantially generated in the production method of the
present invention. Therefore, according to the production method of
the present invention, antimicrobials, fungicides, or bulk
pharmaceuticals or agrochemicals can be efficiently produced
compared to conventional art.
EXAMPLES
[0071] The present invention is explained in the following by
referring to Example, which are not to be construed as limitative.
NMR apparatus used for analysis in Example is JNM-ECP400 (400 MHz)
manufactured by JEOL Ltd. The unit of yield (%) described in
Example is mol %.
Example 1
Synthesis of Compound (a1)
##STR00012##
[0073] Sulfur monochloride (5.40 g, 40 mmol) was placed in a
reactor. The reactor inside was kept under nitrogen atmosphere, and
the system in the below-mentioned reaction was also kept in a
non-aqueous state (moisture content: 1000 mass ppm or less).
[0074] First, a non-aqueous solution containing compound (c.sup.1)
(1.74 g, 10 mmol), monochlorobenzene (13.4 g) and pyridine (0.12 g,
1.5 mmol) was prepared.
[0075] Next, 1/5 volume of the non-aqueous solution was placed in
the reactor while the solution in the reactor was stirred, and the
solution in the reactor was heated at 80 to 90.degree. C. for 10
min, and then cooled to 25.degree. C. Then, the residual
non-aqueous solution (4/5 volume) was placed in the reactor, and
the obtained solution in the reactor was stirred at 25.degree. C.
for 22 hr. Then, the solution was stirred at 137.degree. C. for 27
hr. The obtained solution in the reactor was analyzed by
.sup.19F-NMR (internal standard material:
3,4,5-trichlorobenzotrifluoride), and thereby, the production of
compound (a.sup.1) was confirmed. The yield of compound (a.sup.1)
was 88% on the basis of the used amount of compound (c.sup.1).
INDUSTRIAL APPLICABILITY
[0076] As is clear from the above-mentioned results, according to
the production method of the present invention, compound (a), i.e.,
a fluorine-containing pyrazolecarboxylic acid halide, can be
obtained in a high-yield of 80% or more, from compound (c), i.e., a
fluorine-containing pyrazolylalkylketone, by one-step reaction.
* * * * *